Process for the production of optically active 4-aryl-2-pyrrolidinones

ABSTRACT

PCT No. PCT/DE91/00773 Sec. 371 Date Jul. 1, 1992 Sec. 102(e) Date Jul. 1, 1992 PCT Filed Sep. 27, 1991 PCT Pub. No. WO92/06077 PCT Pub. Date Apr. 16, 1992.Stereoselective process for the production of (4R)- or (4S)-4-aryl-2-pyrrolidinones as well as intermediate products and the stereoselective process for the production of the optically active intermediate compounds.

SUMMARY OF THE INVENTION

The invention relates to the process for the production of opticallyactive 4-aryl-2-pyrrolidinones as well as the process for the productionof the optically active initial compounds, which are suitable asintermediate products for the production of 4S or 4R enantiomers of4-aryl-2-pyrrolidinones.

It is known from U.S. Pat. No. 4,012,495 and from WO 86/02268, that4-aryl-2-pyrrolidinones are compounds with good effectiveness, which aresuitable for the treatment of neuroleptic and mental disorders and canalso be used for topical treatment of inflammations.

From among the 4-aryl-2-pyrrolidinones, the4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidinone was thoroughlypharmacologically studied. By means of a very costly process and aprocess that cannot be duplicated on an industrial scale, this compoundwas converted into its optical antipode and it was noted that bothenantiomers represent pharmacologically effective compounds.

Since it is desirable that in chiral active ingredients ofpharmaceutical agents only one antipode each is used for the productionof pharmaceutical preparations, the object was to develop anindustrially applicable process for the production of optically active4-aryl-2-pyrrolidinones.

According to the process of the invention the desired (4S)-or(4R)-4-aryl-2-pyrrolidinones can be produced in a simple synthesis fromthe easily accessible optically active initial compounds and can beisolated in high optical purity and good yield without costly separativeoperations. The recovery of the auxiliary material is to be consideredas an additional advantage of the process according to the invention.

The invention relates to a process for the production of (4S)- or(4R)-4-aryl-2-pyrrolidinones of formula I ##STR1## in which

R¹ is a hydrogen or a hydrocarbon radical with up to 7 carbon atomsoptionally interrupted with an oxygen atom and

R² is a C₁₋₄ alkyl characterized in that an optically active compound offormula II ##STR2## in which

R¹ has the meaning of R1 or represents an easily cleavable group and

    R.sup.2 is a C.sub.1-4 alkyl

is catalytically reduced with hydrogen, and cyclized and the easilycleavable group is optionally cleaved off and the thus obtained hydroxygroup is etherified.

As hydrocarbon radical R¹, saturated or unsaturated, straight-chain orbranched alkyl groups with 1-6 carbon atoms, preferably 1-4 carbonatoms, are suitable, also C₄₋₆ -cycloalkylalkyl and cycloalkyl groupswith 3-7 carbon atoms and the benzyl group as well as cycloalkyl groupsinterrupted by an oxygen atom.

As saturated alkyl groups, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec. butyl, tert. butyl, pentyl,2,2-dimethylpropyl and hexyl each are suitable.

As alkenyl and alkynyl groups there can preferably be mentioned:2-propenyl, 2-propinyl. If hydrocarbon radical R¹ means a cycloalkylgroup, then cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl are meant, preferably C₃₋₅ -cycloalkyl groups.Cyclopropylmethyl, cyclopropylethyl and cyclopentylmethyl are to beconsidered as preferred for the cycloalkylalkyl group.

If the hydrogen carbon radical is interrupted by an oxygen atom, thenthe cycloalkyl radical, in which a CH₂ group is replaced by an oxygenatom is especially meant, and as cyclic ether radical, for example,3-tetrahydrofuranyl and 3-tetrahydropyranyl can be mentioned.

If the molecule contains a cyclic ether radical, thus another asymmetriccenter can be present that can be converted to the antipodes in theusual way.

The phrase "easily cleavable group" within the scope of this inventionmeans that the hydroxy protective group is easily cleavable in the usualway either under the reaction conditions or subsequently. As protectivegroups, for example, the methoxymethyl, methoxy-ethoxymethyl and alsothe benzyl group can be mentioned.

As catalysts for the reaction according to the invention thehydrogenation catalysts usually used are suitable such as, for example,Raney nickel or noble metal catalysts such as platinum oxide andpalladium/carbon. The reaction takes place at room temperature or withheating to 50° C. at hydrogen standard pressure or elevated hydrogenpressure (about 50 bars) in an aqueous suspension or in inert solventssuch as alcohols, ethers or ketones or their mixtures. Generally thereaction is complete after 1 to 10 hours.

If easily cleavable groups, possibly present, are to be cleaved off inthe course of the reaction according to the invention, hydrogenation isperformed suitably for some time, optionally under pressure or saidgroups are cleaved off with acid in the usual way.

The etherification of the hydroxy compound can be performed according tothe processes described in U.S. Pat. No. 4,012,495. For example, theetherification takes place by reaction with a suitable tosylate,mesylate or halide in the presence of a base with alkali hydroxides andalkali carbonates and tetrabutyl ammonium hydrogen sulfate in inertsolvents, such as dimethyl sulfoxide, dimethyl formamide, acetonitrile,tetrahydrofuran, methylene chloride or alcohols at room temperature tothe boiling point of the solvent.

The invention further relates to the compounds of formula II, which areoptically active initial compounds, from which the compounds of formulaI are obtained in one reaction step with very high optical purity.

The invention also relates tot he process for the production of thecompounds of formula II, characterized in that an optically activecompound of formula III ##STR3## and a compound of formula IV ##STR4##in which R^(1') and R² have the above meaning, are added.

The addition takes place in the way of a Michael addition, by formingthe enolate anion of compound III with strong bases and adding it to theolefin.

The reaction takes place at low temperatures (-110° C. to -40° C.) inaprotic solvents such as cyclic ethers, for example, dioxane ortetrahydrofuran. As bases, for example, alkali salts such as sodium,potassium or lithium salts of hexamethyldisilazane, diisopropylamine ortetramethylpiperidine or hydrides and alcoholates of the mentionedalkali metals are suitable.

Depending on the position of the benzyl group on the oxazolidinone offormula III, after the addition of the olefin, the antipode is obtainedin high yields and high optical purity after recrystallization.

Suitably all reactions described here are performed under a protectivegas atmosphere, for example, under nitrogen or argon.

The compounds of formulas III and IV used in the process according tothe invention as starting material are known compounds or analogues ofknown compounds, which can be produced stereoselectively according toknown methods.

The initial compound of formula III can be produced after acetylation of(4S)- or (4R)-4-benzyl-2-oxazolidinone according to usual methods. Theacetylation can be performed, for example, in the presence of strongbases such as butyllithium, lithium diisopropylamide, NaH i.a., inaprotic solvents such as cyclic ethers or hydrocarbons or in thetwo-phase system according to methods described by V. Illi Synthesis1979, 387.

The initial compounds of formula IV can be synthesized, e.g. by aldolcondensation of the aldehyde with nitromethane (C. B. Gairand, G. R.Lappin J. Org. Chem. 18. 1 (1953))

The following examples are to explain the process according to theinvention.

Production of the Initial Compounds

1) 2-(3-Benzyloxy-4-methoxy-phenyl)-1-nitro-(E)-ethane

10 g (41.3 mmol) of 3-benzyloxy-4-methoxy-benzaldehyde, 3.2 g (41.5mmol, 1 eq) of ammonium acetate and 12 ml of nitromethane are dissolvedin 50 ml of glacial acetic acid and refluxed for 12 hours. Aftercooling, the mixture is concentrated by evaporation in a vacuum, mixedwith a little water and shaken out several times with ethyl acetate.After drying on sodium sulfate, the solvent is removed in a water jetvacuum. The solid residue can be recrystallized in ethyl acetate/hexane.The yield is 8.56 g (73%) of golden yellow platelet shaped crystals witha melting point of 126° C.

2) (4S)-3-Acetyl-4-(benzyl)-2-oxazolidinone

10 g (56.4 mmol) of (4S)-4-benzyl-2-oxazolidinone is dissolved underargon atmosphere in 100 ml of abs. THF and is mixed dropwise at -78° C.with 37 ml (59.3 mmol, 1.6M in hexane, 1.05 eq) of n-butyllithium. After10 min., 4.1 ml (4.5 g, 57.5 mmol, 1.02 eq) of acetyl chloride isinstilled. The solution is stirred for 15 more min. under cooling andthen 3 hours at room temperature. For working up it is mixed with 50 mlof saturated ammonium chloride solution, the organic solvents aredistilled off in a vacuum and the remaining residue is extracted severaltimes with ethyl acetate. After drying on sodium sulfate andconcentration by evaporation in a vacuum, the remaining solid isrecrystallized in ethyl acetate/hexane. 10.3 g (83%) of colorlessneedles with melting point of 106° C. is formed.

EXAMPLE 1

a) (4S,3'R) and (4S,3'S)-3-(3'-(3-Benzyloxy-4methoxyphenyl)-4'-nitrobutanoicacid)-4-benzyl-2-oxazolidinone

3 g (16.9 mmol, 1 eq.) of (4S)-3-acetyl-4-benzyl-2-oxazolidinonedissolved in 10 ml of abs. THF is within 10 minutes in a suspension of3.1 g (16.9 mmol) of sodium hexamethyldisilazane in 150 ml of abs. THFunder argon atmosphere at -78° C. The batch is stirred for 30 minutesand then mixed with a solution of 4.8 g (16.8 mmol, 1 eq) of olefin and50 ml of abs. THF within one hour. The reaction mixture is stirredanother 6 hours with cooling and then heated slowly to room temperature.The reaction is stopped with addition of 50 ml saturated ammoniumchloride solution, the organic solvent is removed in a vacuum, theaqueous phase is shaken out with ethyl acetate and the resulting organicfractions are dried on sodium sulfate. The crude product freed from thesolvent contains, according to analytic HPLC, (0.6% isopropanol/hexane,flow 2 ml/min. 5 μ Nucleosil 50, 4*250, UV-detection (254 nm) bothdiastereomers (4S, 3'S) (RT.: 8.45 min) and (4S, 3'R) (RT.: 11.61 min.)in a ratio of 6:94 (de=88%). By a single recrystallization from ethylacetate/hexane 5.5 g (65%) of a colorless, fine crystalline substancewith a melting point of 153° C. is obtained, which according to analyticHPLC has a diastereomeric ratio of (4S, 3'S):(4S, 3'R)=0.5:99.5(de=99%).

(4S, 3'R) - oxazolidinone derivative

[α]_(D) ²⁰ =+28.05 (c=2.3, chloroform)

(4S, 3'S) - oxazolidinone derivative

[α]_(D) ²⁰ =+43.8 (c=1, chloroform) melting point: 132° C.

b) (4S)-4-(3-Benzyloxy-4-methoxy-phenyl)-2-pyrrolidinone

A suspension of 2 g (3.96 mmol) of (4S, 3'R)-oxazolidinone obtainedaccording to a) and 2 ml of Raney nickel (suspension in water) is shakenout under a hydrogen pressure of 2 bars for 6 hours at room temperature.Then the catalyst is filtered off, the solvent is drawn off and thecrude product is subjected to a column chromatographic purification(methylene chloride/acetone, 7:3).

Isolated are:

    ______________________________________                                        440 mg of (4S)*4-(-3-benzyloxy-4 methoy phenyl)-2-pyrrolidinone               [α].sub.D.sup.20 = +28.65 (c = 0.5, chloroform) melting point:          121° C.                                                                320 mg of (4S)-4-(-3-hydroxy-4-methoxy-phenyl)-2-pyrrolidinone                [α].sub.D.sup.20 = +36.7 (c = 1.8, chloroform) melting point            145° C.                                                                470 mg of (4S)-4-benzyl-2-oxazolidinone, melting point 86°             ______________________________________                                        C.                                                                        

I claim:
 1. A process for production of an optically active4-aryl-2-pyrrolidinone of formula I ##STR5## wherein R¹ is hydrogen or ahydrocarbon radical with up to 7 carbon atoms and optionally interruptedwith an oxygen atom; andR² is C₁₋₄ -alkyl, said process comprising:catalystically reducing with hydrogen and cyclizing, inthe presence of ahydrogenation catalyst, an optically active compound of formula II##STR6## wherein R^(1') has the meaning of R¹ or is a cleavable hydroxyprotective group, and R² is C₁₋₄ -alkyl, andoptionally cleaving off saidcleavable hydroxy protective group and etherifying the resultant hydroxygroup, to obtain a compound of formula I.
 2. An optically activecompound of formula II ##STR7## wherein R^(1') is hydrogen, ahydrocarbon radical having up to 7 carbon atoms and optionallyinterrupted with an oxygen atom, or a cleavable hydroxy protectivegroup, andR² is C₁₋₄ -alkyl.
 3. A process for production of a compoundof formula II ##STR8## wherein R^(1') is hydrogen, a hydrocarbon radicalhaving up to 7 carbon atoms and optionally interrupted with an oxygenatom, or a cleavable hydroxy protective group, andR² is C₁₋₄-alkyl,comprising performing a Michael addition, in the presence of abase, between an optically active compound of formula III ##STR9## and acompound of formula IV ##STR10## wherein R^(1') and R² have the meaningsindicated above.
 4. A process according to claim 1, wherein R¹ is asaturated or unsaturated, straight-chain or branched alkyl group having1-6 carbon atoms, a C₄₋₆ -cycloalkylalkyl, a C₃₋₇ -cycloalkyl, a C₃₋₇-cycloalkyl which is interrupted by an oxygen atom, or benzyl.
 5. Aprocess according to claim 4, wherein R¹ is a saturated or unsaturated,straight-chain or branched alkyl group having 1-6 carbon atoms.
 6. Aprocess according to claim 5, wherein R¹ is a saturated or unsaturated,straight-chain or branched alkyl group with 1-4 carbon atoms.
 7. Aprocess according to claim 4, wherein R¹ is methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert.-butyl, pentyl,2,2-dimethylpropyl, hexyl, 2-propenyl, 2-propinyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl,cyclopropylethyl, cyclopentylmenthyl, 3-tetrahydrofuranyl or3-tetrahydropyranyl.
 8. A process according to claim 1, whereincatalytic reduction with hydrogen and cyclization is performed in thepresence of Raney nickel, platinum oxide or palladium/carbon.
 9. Aprocess according to claim 4, wherein catalytic reduction with hydrogenand cyclization is performed in the presence of Raney nickel, platinumoxide or palladium/carbon.
 10. A process according to claim 1, whereincatalytic reduction with hydrogen and cyclization is conducted in anaqueous suspension.
 11. A process according to claim 1, whereincatalytic reduction with hydrogen and cyclization is conducted in aninert solvent.
 12. A process according to claim 1, wherein R^(1') is acleavable hydroxy protective group which is cleaved off during catalyticreduction with hydrogen and cyclization.
 13. A process according toclaim 1, wherein R^(1') is a cleavable hydroxy protective group and,after catalytic reduction with hydrogen and cyclization, R^(1') iscleaved off and the resultant hydroxy group is etherified.
 14. A processaccording to claim 12, wherein R¹ is methoxymethyl, methoxyethoxymethylor benzyl.
 15. A process according to claim 13, wherein R¹ ismethoxymethyl, methoxyethoxymethyl or benzyl.
 16. A process according toclaim 12, wherein etherification is conducted in the presence of a basein an inert solvent.
 17. A process according to claim 1, wherein R^(1')is R¹.
 18. A process according to claim 4, wherein R^(1') is R¹.
 19. Aprocess according to claim 3, wherein said Michael addition is conductedat a temperature of -110°--40° C. in an aprotic solvent.
 20. A processfor production of an optically active 4-aryl-2-pyrrolidinone of formulaI ##STR11## wherein R¹ is hydrogen or a hydrocarbon radical with up to 7carbon atoms and optionally interrupted with an oxygen atom; andR² isC₁₋₄ -alkyl,said process comprising: performing a Michael addition, inthe presence of a base, between an optically active compound of formulaIII ##STR12## and a compound of formula IV ##STR13## wherein R^(1') ishydrogen, a hydrocarbon radical having up to 7 carbon atoms andoptionally interrupted with an oxygen atom, or is a cleavable hydroxyprotective group, and R² is C₁₋₄ -alkyl,to obtain diastereomers offormula II ##STR14## catalytically reducing with hydrogen and cyclizing,in the presence of a hydrogenation catalyst, an optically activecompound of formula II; and optionally cleaving off said cleavablehydroxy protective group and etherifying the resultant hydroxy group toobtain a compound of formula I.